Expert Critique

FROM THE ASCO Reading Room

Vinay Gupta, MDOncologySaint Luke's Cancer InstituteKansas City, MO

The outcomes for patients with Stage III non-small cell lung carcinoma remain dismal owing to the high recurrence rates seen after definitive chemoradiation. This is a heterogeneous population, and multiple factors affect prognosis.

Patients who are able to ultimately undergo surgical resection do have a better prognosis. Overall, studies have documented improved outcomes in patients with superior performance status and clinical response to initial chemoradiation, who are younger, and who have non-squamous histology. Clinical trials for consolidation therapy with ALK/EGFR inhibitors or with PD-1/PD-L1 antibodies are underway and forthcoming, respectively.

At recurrence, oligometastatic disease behooves an aggressive approach, with application of stereotactic radiosurgery and/or surgery demonstrated to result in a better prognosis. Overall, an individualized approach to each patient, within a multidisciplinary setting, will allow us to better care for our Stage III lung cancer patients.

Full Critique

Disease recurrence is all too common in patients with stage III non-small cell lung cancer (NSCLC) who undergo deﬁnitive chemoradiation therapy. As a result, determining which patients will benefit most from salvage therapy is key, and that means pinpointing the clinical parameters at the time of recurrence that are associated with improved survival.

One question lung cancer specialists must answer is whether some of those factors are more meaningful than others.

In one study of 58 NSCLC patients treated for locally advanced stage III, locally recurrent disease, and postoperative gross residual NSCLC, 21 had recurrent disease. The authors reported that based on their multivariate analysis of the definitive chemoradiation arm, the significant prognostic factors for overall survival were the use of consolidation chemotherapy (P=0.022), biologically equivalent dose 10 (P=0.007), and a clinical tumor response (P=0.030).

For Benjamin Movsas, MD, of Henry Ford Hospital in Detroit, performance status is very important, but there also are other aspects that need to be considered: "For example, what was the disease-free interval? How long the patient did well before disease recurrence is a very important factor. Studies have suggested that the longer the patient does well after initial treatment, the more likely the patient may benefit from additional intervention."

For instance, a 2006 study calculated a median disease-free interval of 5 months in advanced-stage NSCLC patients with recurrent disease who were initially managed with definitive radiation or chemoradiation. The authors noted that the median postoperative survival was 30 months, and the estimated 3-year survival was 47%.

In addition, a longer survival was seen among patients undergoing early salvage resection for abnormal FDG-PET than for those with obvious relapse based on CT studies (43 versus 12 months, P=0.019).

"Moreover, we should look at the number of sites of recurrence," Movsas continued. "Is it one area of recurrence or three, or five, or more than 10? What is the threshold or cut-off regarding prognosis? I don't think we know the answer to that yet, but we do know that fewer is better than more sites of recurrence. This becomes very important in the context of what we consider oligometastatic -- or limited metastatic -- disease."

Movsas cited a 2014 meta-analysis of 757 NSCLC patients with oligometastatic disease, which showed that with the use of stereotactic radiation or surgery, the 5-year survival rate was about 30%. He called that rate "remarkably good. While this was not a randomized study, it suggests that there may be an opportunity to catch the disease in this interim – oligometastatic – state. More research is needed in this area."

Other experts have called for aggressive treatment of oligometastatic disease. An analysis from the University of Rochester in N.Y. demonstrated that the median survivals of patients with limited stage IV metastatic NSCLC treated with hypofractionated, image-guided radiotherapy was similar to that of stage III NSCLC patients, with a 5-year survival rate of 14%.

Patients who have one or two sites of recurrence, a longer time to recurrence, a lower nodal burden, and a greater performance status, are generally the ones who do better with aggressive treatment, said Daniel Gomez, MD, of MD Anderson Cancer Center in Houston.

Movsas noted that at Henry Ford, such "complex" NSCLC patients are presented before the multidisciplinary thoracic oncology tumor board, which is made up of radiation oncologists, medical oncologists, thoracic surgeons, and other healthcare providers.

One key goal is to find the crucial "therapeutic window" where local therapies, such as stereotactic body radiation therapy or surgery, could be selectively and thoughtfully applied to increase the chance for more durable local control down the road, he said.

Future advances in fine-tuning prognostic factors could also include looking at patient survival in the context of how long patients have already survived after treatment. "So often the question is, at the time of diagnosis, how long will a patient live with this particular set of prognostic factors?," Gomez explained. "If we look at a patient who has already lived a year, we ask, 'What's the chance they will survive 5 years?'"

Gomez and colleagues did just that in a 2015 study, analyzing overall (OS) and disease-free survival (DFS) in stage III patients after definitive chemoradiation using two statistical methods. One used diagnosis as the index date, while the other used "conditional survival analysis, with a variety of disease-free index dates." The researchers then determined whether prognostic factors varied based on the reference date.

Based on the conditional survival analysis, there was an increase in 5-year OS after 6 months, with conditional survival after 30 months approaching 100%.

"What we showed is that the actual magnitude of benefit is unique based on one of the two analyses," Gomez said. "So at diagnosis, what are factors that are associated with 5-year survival, versus if we take a more dynamic time point -- let's say a patient survived 'x' amount of time -- what's the chance they will survive 4 more years? That can sometimes lead to different results."

The reason for that difference is that, as time goes on, certain prognostic factors become less important, he explained. "So in the first 6 or 12 months, all of those prognostic factors are important. But if a patient gets past those 12 months, then some of those factors become of less consequence."

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